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Titolo:
POLYGLUTAMYLATION OF THE DIHYDROFOLATE-REDUCTASE INHIBITOR GAMMA-METHYLENE-10-DEAZAAMINOPTERIN IS NOT ESSENTIAL FOR ANTITUMOR-ACTIVITY
Autore:
CAO S; ABRAHAM A; NAIR MG; PATI R; GALIVAN JH; HAUSHEER FH; RUSTUM YM;
Indirizzi:
UNIV SO ALABAMA,DEPT BIOCHEM & MOLEC BIOL MOBILE AL 36688 UNIV SO ALABAMA,DEPT BIOCHEM & MOLEC BIOL MOBILE AL 36688 BIONUMER PHARMACEUT INC SAN ANTONIO TX 78229 ROSWELL PK CANC INST BUFFALO NY 14263 NEW YORK STATE DEPT HLTH,WADSWORTH CTR LABS & RES ALBANY NY 12201
Titolo Testata:
Clinical cancer research
fascicolo: 4, volume: 2, anno: 1996,
pagine: 707 - 712
SICI:
1078-0432(1996)2:4<707:POTDIG>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
METHOTREXATE POLYGLUTAMATES; GAMMA-FLUOROMETHOTREXATE; THYMIDYLATE SYNTHASE; BIOLOGICAL-ACTIVITY; DERIVATIVES; INVITRO; ANALOGS; CELLS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
27
Recensione:
Indirizzi per estratti:
Citazione:
S. Cao et al., "POLYGLUTAMYLATION OF THE DIHYDROFOLATE-REDUCTASE INHIBITOR GAMMA-METHYLENE-10-DEAZAAMINOPTERIN IS NOT ESSENTIAL FOR ANTITUMOR-ACTIVITY", Clinical cancer research, 2(4), 1996, pp. 707-712

Abstract

As part of a continuing program aimed at developing nonpolyglutamylatable inhibitors of dihydrofolate reductase that are less toxic and more specific in their action, we herein report the therapeutic efficacy and toxicity of gamma-methylene-10-deazaaminopterin (MDAM) in athymic nude mice bearing advanced human HCT-8 ileocecal xenografts and its antitumor activity in C57BL/6 x DBA/2 F-1 (hereafter called B6D2F(1)) mice hearing P388 murine leukemia, For the xenograft study, MDAM was administered at the maximum tolerated dose by the following dose schedules: (a) 5-day continuous i.v. infusion at 1.0 mg/kg/day (schedule I); and (b) i.v. push, daily for 5 days at 50 mg/kg/day (schedule II), The maximum tolerated dose values for methotrexate (MTX) under these conditions were 0.2 and 1.0 mg/kg/day for schedule I and schedule II, respectively, MTX did not exhibit any significant antitumor activity in this model system by both schedules; however, MDAM induced complete responses of 13 and 25% and partial responses of 25 and 50% by schedules I and II, respectively, MDAM also exhibited antitumor activity significantly superior to that of MTX in the P388 tumor model, One of the enantiomers of MDAM, which possesses the natural configuration at the gamma-methyleneglutamate moiety (L-MDAM), has been shown to be a better inhibitor of human recombinant dihydrofolate reductase and H35 hepatoma cell growth than D,L-MDAM, L-MDAM inhibited the uptake of radiolabeled folinic acid to H35 hepatoma cells eight times more efficiently than MTX, The results indicate that the superior activity of MDAM relative to MTX may be partially due to a combination of enhanced transport to tumor cells and slower deactivation by aldehyde oxidase.

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Documento generato il 12/07/20 alle ore 11:28:29